ABSTRACT As one of the largest opioid consuming countries in the world, the prevalence of opioid use disorder (OUD) during 2017 is over 5 million in the U.S. alone. The significant increase of opioids use disorder (OUD) cases during the last 2 decades may be partially attributed to our overreliance on the prescription of the opioids for the management of non-cancer chronic pain, such as osteoarthritis (OA) pain. The extensive use of opioids for pain management can be associated with a variety of side effects including constipation, nausea, dizziness, vomiting, liver damage, respiratory depression leading to brain damage due to the hypoxia, and physical dependence, tolerance and addiction. The higher dose prescription because of the physical dependence and tolerance leading to OUD and the intertwined heroin use related with the addiction have been reported. Therefore, the goals of the project are to develop, translate and commercialize a novel non-opioid therapy for sustained, effective, safe management of OA pain, and to prevent opioids use disorder among osteoarthritis patients. Through an innovative structural design, we have developed a N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone (Dex) prodrug (P-Dex-H) that is a free-flowing aqueous solution at reduced temperature, but becomes a hydrogel (ProGel) when the temperature is raised to > 30 ?C. This thermoresponsive phase transition property allows the macromolecular prodrug formulation to be deposited in the synovial cavity with sustained presence for a protracted period of time. With continuous exposure to the synovial fluid, we have shown that the ProGel can then gradually solubilize and release after which it is internalized by synovial phagocytic cells and activated subcellularly to release Dex. In the preliminary studies, we have found that the P-Dex-H-based ProGel was able to provide sustained (> 1 month) amelioration to the joint pain models of adjuvant-induced arthritis (AA), monoarticular adjuvant-induced arthritis (MAA) and monoiodoacetate-induced osteoarthritis (MIA). Furthermore, typical glucocorticoid side effects, such as osteopenia, adrenal gland atrophy were not associated with ProGel treatment. Injection site reactions (e.g., arthralgia), as seen in the case of Flexion Therapeutics? Zilretta? (triamcinolone acetonide extended-release formulation) was also absent in animals treated with ProGel. However, ProGel formulations have not been evaluated in a clinically relevant osteoarthritis model such as the surgical destabilization of the medial meniscus (DMM) mouse model. Therefore, in the Phase I of this fast-track project, we propose to test the feasibility of using ProGel to treat arthritis pain in the DMM mouse model. A thorough physicochemical characterization, including the construction of the phase diagram for ProGel will also completed in preparation for the optimization of the formulation. For Phase II, we proposed to optimize the ProGel formulation by adjusting a variety of structural parameters with the goal of identifying an optimized formulation with the most potent and sustained joint pain amelioration and minimal toxicity. The IND enabling PK/BD study of this optimized ProGel formulation will then be performed. The successful completion of the proposed research will help the ProGel technology to become IND ready for further clinical evaluation.